The gut-brain axis is the relationship between the GI tract and brain function and development
The gut–brain axis is the biochemical signaling that takes place between the gastrointestinal tract (GI tract) and the central nervous system (CNS). The term "gut–brain axis" is occasionally used to refer to the role of the gut flora in the interplay as well, whereas the term "microbiome–gut–brain axis" explicitly includes the role of gut flora in the biochemical signaling events that take place between the GI tract and CNS.
Broadly defined, the gut-brain axis includes the central nervous system, neuroendocrine and neuroimmune systems, including the hypothalamic–pituitary–adrenal axis (HPA axis), sympathetic and parasympathetic arms of the autonomic nervous system, including the enteric nervous system and the vagus nerve, and the gut microbiota. The first of the brain-gut interactions shown, was the cephalic phase of digestion, in the release of gastric and pancreatic secretions in response to sensory signals, such as the smell and sight of food. This was first demonstrated by pavlov.
Interest in the field was sparked by a 2004 study showing that germ-free mice showed an exaggerated HPA axis response to stress compared to non-GF laboratory mice.
As of October 2016, most of the work that had been done on the role of gut flora in the gut-brain axis had been conducted in animals, or on characterizing the various neuroactive compounds that gut flora can produce. Studies with humans – measuring variations in gut flora between people with various psychiatric and neurological conditions or when stressed, or measuring effects of various probiotics (dubbed "psychobiotics" in this context) – had generally been small and were just beginning to be generalized. Whether changes to gut flora are a result of disease, a cause of disease, or both in any number of possible feedback loops in the gut-brain axis, remained unclear.
Gut flora
Bifidobacterium adolescentis Gram
Lactobacillus sp 01
The gut flora is the complex community of microorganisms that live in the digestive tracts of humans and other animals. The gut metagenome is the aggregate of all the genomes of gut microbiota. The gut is one niche that human microbiota inhabit.
In humans, the gut microbiota has the largest numbers of bacteria and the greatest number of species compared to other areas of the body. In humans the gut flora is established at one to two years after birth, and by that time the intestinal epithelium and the intestinal mucosal barrier that it secretes have co-developed in a way that is tolerant to, and even supportive of, the gut flora and that also provides a barrier to pathogenic organisms.
The relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship. Human gut microorganisms benefit the host by collecting the energy from the fermentation of undigested carbohydrates and the subsequent absorption of short-chain fatty acids (SCFAs), acetate, butyrate, and propionate. Intestinal bacteria also play a role in synthesizing vitamin B and vitamin K as well as metabolizing bile acids, sterols, and xenobiotics. The systemic importance of the SCFAs and other compounds they produce are like hormones and the gut flora itself appears to function like an endocrine organ, and dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.
The composition of human gut flora changes over time, when the diet changes, and as overall health changes.
Enteric nervous system
The enteric nervous system is one of the main divisions of the nervous system and consists of a mesh-like system of neurons that governs the function of the gastrointestinal system; it has been described as a "second brain" for several reasons. The enteric nervous system can operate autonomously. It normally communicates with the central nervous system (CNS) through the parasympathetic (e.g., via the vagus nerve) and sympathetic (e.g., via the prevertebral ganglia) nervous systems. However, vertebrate studies show that when the vagus nerve is severed, the enteric nervous system continues to function.In vertebrates, the enteric nervous system includes efferent neurons, afferent neurons, and interneurons, all of which make the enteric nervous system capable of carrying reflexes in the absence of CNS input. The sensory neurons report on mechanical and chemical conditions. Through intestinal muscles, the motor neurons control peristalsis and churning of intestinal contents. Other neurons control the secretion of enzymes. The enteric nervous system also makes use of more than 30 neurotransmitters, most of which are identical to the ones found in CNS, such as acetylcholine, dopamine, and serotonin. More than 90% of the body's serotonin lies in the gut, as well as about 50% of the body's dopamine and the dual function of these neurotransmitters is an active part of gut-brain research.
The first of the gut-brain interactions was shown to be between the sight and smell of food and the release of gastric secretions, known as the cephalic phase, or cephalic response of digestion.[4][5]
Gut-brain integration
The gut–brain axis, a bidirectional neurohumoral communication system, is important for maintaining homeostasis and is regulated through the central and enteric nervous systems and the neural, endocrine, immune, and metabolic pathways, and especially including the hypothalamic–pituitary–adrenal axis (HPA axis). That term has been expanded to include the role of the gut flora as part of the "microbiome-gut-brain axis", a linkage of functions including the gut flora.Interest in the field was sparked by a 2004 study (Nobuyuki Sudo and Yoichi Chida) showing that germ-free mice (genetically homogeneous laboratory mice, birthed and raised in an antiseptic environment) showed an exaggerated HPA axis response to stress compared to non-GF laboratory mice.
The gut flora can produce a range of neuroactive molecules, such as acetylcholine, catecholamines, γ-aminobutyric acid, histamine, melatonin, and serotonin, which is essential for regulating peristalsis and sensation in the gut. Changes in the composition of the gut flora due to diet, drugs, or disease correlate with changes in levels of circulating cytokines, some of which can affect brain function. The gut flora also release molecules that can directly activate the vagus nerve which transmits information about the state of the intestines to the brain.
Likewise, chronic or acutely stressful situations activate the hypothalamic–pituitary–adrenal axis, causing changes in the gut flora and intestinal epithelium, and possibly having systemic effects. Additionally, the cholinergic anti-inflammatory pathway, signaling through the vagus nerve, affects the gut epithelium and flora. Hunger and satiety are integrated in the brain, and the presence or absence of food in the gut and types of food present, also affect the composition and activity of gut flora.
That said, most of the work that has been done on the role of gut flora in the gut-brain axis has been conducted in animals, including the highly artificial germ-free mice. As of 2016 studies with humans measuring changes to gut flora in response to stress, or measuring effects of various probiotics, have generally been small and cannot be generalized; whether changes to gut flora are a result of disease, a cause of disease, or both in any number of possible feedback loops in the gut-brain axis, remains unclear.
Research
Probiotics
A 2016 systematic review of laboratory animal studies and preliminary human clinical trials using commercially available strains of probiotic bacteria found that certain species of the Bifidobacterium and Lactobacillus genera (i.e., B. longum, B. breve, B. infantis, L. helveticus, L. rhamnosus, L. plantarum, and L. casei) had the most potential to be useful for certain central nervous system disorders.Anxiety and mood disorders
As of 2018 work on the relationship between gut flora and anxiety disorders and mood disorders, as well as trying to influence that relationship using probiotics or prebiotics (called "psychobiotics"), was at an early stage, with insufficient evidence to draw conclusions about a causal role for gut flora changes in these conditions, or about the efficacy of any probiotic or prebiotic treatment.People with anxiety and mood disorders tend to have gastrointestinal problems; small studies have been conducted to compare the gut flora of people with major depressive disorder and healthy people, but those studies have had contradictory results.
Much interest was generated in the potential role of gut flora in anxiety disorders, and more generally in the role of gut flora in the gut-brain axis, by studies published in 2004 showing that germ-free mice have an exaggerated HPA axis response to stress caused by being restrained, which was reversed by colonizing their gut with a Bifidobacterium species. Studies looking at maternal separation for rats shows neonatal stress leads to long-term changes in the gut microbiota such as its diversity and composition, which also led to stress and anxiety-like behavior. Additionally, while much work had been done as of 2016 to characterize various neurotransmitters known to be involved in anxiety and mood disorders that gut flora can produce (for example, Escherichia, Bacillus, and Saccharomyces species can produce noradrenalin; Candida, Streptococcus, and Escherichia species can produce serotonin, etc) the inter-relationships and pathways by which the gut flora might affect anxiety in humans were unclear.
